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IGF-1 decreases portal vein endotoxin via regulating intestinal tight junctions and plays a role in attenuating portal hypertension of cirrhotic rats.

Zhao TY, Su LP, Ma CY, Zhai XH, Duan ZJ, Zhu Y, Zhao G, Li CY, Wang LX, Yang D - BMC Gastroenterol (2015)

Bottom Line: LPS decreased TEER in Caco-2 cell monolayer.LPS also decreased claudin-1 and occludin expressions and increased apoptosis in Caco-2 cells.Furthermore, IGF-1 attenuated the effect of LPS on TEER, claudin-1 expression, occludin expression and apoptosis in Caco-2 cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, 116000, Dalian, Liaoning province, China. wwwdxycnbbs@163.com.

ABSTRACT

Background: Intestinal barrier dysfunction is not only the consequence of liver cirrhosis, but also an active participant in the development of liver cirrhosis. Previous studies showed that external administration of insulin-like growth factor 1 (IGF-1) improved intestinal barrier function in liver cirrhosis. However, the mechanism of IGF-1 on intestinal barrier in liver cirrhosis is not fully elucidated. The present study aims to investigate the mechanisms of IGF-1 improving intestinal barrier function via regulating tight junctions in intestines.

Methods: We used carbon tetrachloride induced liver cirrhotic rats to investigate the effect of IGF-1 on intestinal claudin-1 and occludin expressions, serum alanine transaminase (ALT) and aspartate transaminase (AST) levels, severity of liver fibrosis, portal pressures, enterocytic apoptosis and lipopolysaccharides (LPS) levels in portal vein. The changes of IGF-1 in serum during the development of rat liver cirrhosis were also evaluated. Additionally, we assessed the effect of IGF-1 on claudin-1 and occludin expressions, changes of transepithelial electrical resistance (TEER) and apoptosis in Caco-2 cells to confirm in vivo findings.

Results: Serum IGF-1 levels were decreased in the development of rat liver cirrhosis, and external administration of IGF-1 restored serum IGF-1 levels. External administration of IGF-1 reduced serum ALT and AST levels, severity of liver fibrosis, LPS levels in portal vein, enterocytic apoptosis and portal pressure in cirrhotic rats. External administration of IGF-1 increased the expressions of claudin-1 and occludin in enterocytes, and attenuated tight junction dysfunction in intestines of cirrhotic rats. LPS decreased TEER in Caco-2 cell monolayer. LPS also decreased claudin-1 and occludin expressions and increased apoptosis in Caco-2 cells. Furthermore, IGF-1 attenuated the effect of LPS on TEER, claudin-1 expression, occludin expression and apoptosis in Caco-2 cells.

Conclusions: Tight junction dysfunction develops during the development of liver cirrhosis, and endotoxemia will develop subsequently. Correspondingly, increased endotoxin in portal system worsens tight junction dysfunction via decreasing intestinal occludin and claudin-1 expressions and increasing enterocytic apoptosis. Endotoxemia and intestinal barrier dysfunction form a vicious circle. External administration of IGF-1 breaks this vicious circle. Improvement of tight junctions might be one possible mechanism of the restoration of intestinal barrier function mediated by IGF-1.

No MeSH data available.


Related in: MedlinePlus

a Portal pressure of the liver cirrhosis group was higher than that of the control group significantly, and external administration of IGF-1 reduced portal pressure of the liver cirrhosis. b Plasma endotoxin levels of the liver cirrhosis group were higher than those of the control group significantly, and external administration of IGF-1 reduced plasma endotoxin levels of the liver cirrhosis. c TEER values of Caco-2 cell monolayer in LPS group were lower than those of Caco-2 cell monolayer in the control group. IGF-1 increased the TEER values of Caco-2 monolayer as compared with those of the LPS group. Data were shown with the mean ± SD. **P <0.001 vs. control group, ## P <0.001 vs. CCL4 group or LPS group
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Fig3: a Portal pressure of the liver cirrhosis group was higher than that of the control group significantly, and external administration of IGF-1 reduced portal pressure of the liver cirrhosis. b Plasma endotoxin levels of the liver cirrhosis group were higher than those of the control group significantly, and external administration of IGF-1 reduced plasma endotoxin levels of the liver cirrhosis. c TEER values of Caco-2 cell monolayer in LPS group were lower than those of Caco-2 cell monolayer in the control group. IGF-1 increased the TEER values of Caco-2 monolayer as compared with those of the LPS group. Data were shown with the mean ± SD. **P <0.001 vs. control group, ## P <0.001 vs. CCL4 group or LPS group

Mentions: Endotoxin was previously proven to be a precipitating factor in the development of cirrhotic portal hypertension. We postulated that IGF-1 could strengthen intestinal junctions and prevent gut endotoxin from entering portal vein system. Through reducing plasma endotoxin level, IGF-1 could reduce portal hypertension. As expected, portal pressure of the liver cirrhosis group was higher than that of the control group significantly, and external administration of IGF-1 reduced portal pressure of the liver cirrhotic rats (Fig. 3a), which showed that IGF-1 was a negative regulating factor in portal hypertension of liver cirrhosis. Not surprisingly, plasma endotoxin entering portal veins were increased during the development of liver cirrhosis (Fig. 3b), and this effect was via decreased expressions of occludin and claudin-1 in intestines (Fig. 4a, b, c and d),which indicated tight junction dysfunction playing important roles in endotoxemia development of liver cirrhosis. Moreover, external administration of IGF-1 reduced plasma endotoxin levels in portal veins of liver cirrhotic rats (Fig. 3b), and this effect was via increased expressions of occludin and claudin-1 in intestines (Fig. 4a, b, c and d). So IGF-1 improved intestinal tight junction function via upregulating occludin and claudin-1 expressions. With improvement of intestinal tight junction function, endotoxemia would be alleviated. We also used in vitro experiments to confirm our in vivo findings. As expected, LPS reduced the TEER values in Caco-2 cell monolayer (Fig. 3c). Furthermore, we found that IGF-1 increased the TEER values (Fig. 3c) in Caco-2 monolayer through upregulating occludin and caludin-1 expressions (Fig. 4e, f, g and h), which indicated that IGF-1 upregulated these two tight junction proteins in intestinal cells to restore intestinal tight junctions. With this cell experiment, LPS was also proven to be able to cause tight junction dysfunction. Endotoxemia and intestinal barrier dysfunction forms a vicious circle.Fig. 3


IGF-1 decreases portal vein endotoxin via regulating intestinal tight junctions and plays a role in attenuating portal hypertension of cirrhotic rats.

Zhao TY, Su LP, Ma CY, Zhai XH, Duan ZJ, Zhu Y, Zhao G, Li CY, Wang LX, Yang D - BMC Gastroenterol (2015)

a Portal pressure of the liver cirrhosis group was higher than that of the control group significantly, and external administration of IGF-1 reduced portal pressure of the liver cirrhosis. b Plasma endotoxin levels of the liver cirrhosis group were higher than those of the control group significantly, and external administration of IGF-1 reduced plasma endotoxin levels of the liver cirrhosis. c TEER values of Caco-2 cell monolayer in LPS group were lower than those of Caco-2 cell monolayer in the control group. IGF-1 increased the TEER values of Caco-2 monolayer as compared with those of the LPS group. Data were shown with the mean ± SD. **P <0.001 vs. control group, ## P <0.001 vs. CCL4 group or LPS group
© Copyright Policy - open-access
Related In: Results  -  Collection

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Fig3: a Portal pressure of the liver cirrhosis group was higher than that of the control group significantly, and external administration of IGF-1 reduced portal pressure of the liver cirrhosis. b Plasma endotoxin levels of the liver cirrhosis group were higher than those of the control group significantly, and external administration of IGF-1 reduced plasma endotoxin levels of the liver cirrhosis. c TEER values of Caco-2 cell monolayer in LPS group were lower than those of Caco-2 cell monolayer in the control group. IGF-1 increased the TEER values of Caco-2 monolayer as compared with those of the LPS group. Data were shown with the mean ± SD. **P <0.001 vs. control group, ## P <0.001 vs. CCL4 group or LPS group
Mentions: Endotoxin was previously proven to be a precipitating factor in the development of cirrhotic portal hypertension. We postulated that IGF-1 could strengthen intestinal junctions and prevent gut endotoxin from entering portal vein system. Through reducing plasma endotoxin level, IGF-1 could reduce portal hypertension. As expected, portal pressure of the liver cirrhosis group was higher than that of the control group significantly, and external administration of IGF-1 reduced portal pressure of the liver cirrhotic rats (Fig. 3a), which showed that IGF-1 was a negative regulating factor in portal hypertension of liver cirrhosis. Not surprisingly, plasma endotoxin entering portal veins were increased during the development of liver cirrhosis (Fig. 3b), and this effect was via decreased expressions of occludin and claudin-1 in intestines (Fig. 4a, b, c and d),which indicated tight junction dysfunction playing important roles in endotoxemia development of liver cirrhosis. Moreover, external administration of IGF-1 reduced plasma endotoxin levels in portal veins of liver cirrhotic rats (Fig. 3b), and this effect was via increased expressions of occludin and claudin-1 in intestines (Fig. 4a, b, c and d). So IGF-1 improved intestinal tight junction function via upregulating occludin and claudin-1 expressions. With improvement of intestinal tight junction function, endotoxemia would be alleviated. We also used in vitro experiments to confirm our in vivo findings. As expected, LPS reduced the TEER values in Caco-2 cell monolayer (Fig. 3c). Furthermore, we found that IGF-1 increased the TEER values (Fig. 3c) in Caco-2 monolayer through upregulating occludin and caludin-1 expressions (Fig. 4e, f, g and h), which indicated that IGF-1 upregulated these two tight junction proteins in intestinal cells to restore intestinal tight junctions. With this cell experiment, LPS was also proven to be able to cause tight junction dysfunction. Endotoxemia and intestinal barrier dysfunction forms a vicious circle.Fig. 3

Bottom Line: LPS decreased TEER in Caco-2 cell monolayer.LPS also decreased claudin-1 and occludin expressions and increased apoptosis in Caco-2 cells.Furthermore, IGF-1 attenuated the effect of LPS on TEER, claudin-1 expression, occludin expression and apoptosis in Caco-2 cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, 116000, Dalian, Liaoning province, China. wwwdxycnbbs@163.com.

ABSTRACT

Background: Intestinal barrier dysfunction is not only the consequence of liver cirrhosis, but also an active participant in the development of liver cirrhosis. Previous studies showed that external administration of insulin-like growth factor 1 (IGF-1) improved intestinal barrier function in liver cirrhosis. However, the mechanism of IGF-1 on intestinal barrier in liver cirrhosis is not fully elucidated. The present study aims to investigate the mechanisms of IGF-1 improving intestinal barrier function via regulating tight junctions in intestines.

Methods: We used carbon tetrachloride induced liver cirrhotic rats to investigate the effect of IGF-1 on intestinal claudin-1 and occludin expressions, serum alanine transaminase (ALT) and aspartate transaminase (AST) levels, severity of liver fibrosis, portal pressures, enterocytic apoptosis and lipopolysaccharides (LPS) levels in portal vein. The changes of IGF-1 in serum during the development of rat liver cirrhosis were also evaluated. Additionally, we assessed the effect of IGF-1 on claudin-1 and occludin expressions, changes of transepithelial electrical resistance (TEER) and apoptosis in Caco-2 cells to confirm in vivo findings.

Results: Serum IGF-1 levels were decreased in the development of rat liver cirrhosis, and external administration of IGF-1 restored serum IGF-1 levels. External administration of IGF-1 reduced serum ALT and AST levels, severity of liver fibrosis, LPS levels in portal vein, enterocytic apoptosis and portal pressure in cirrhotic rats. External administration of IGF-1 increased the expressions of claudin-1 and occludin in enterocytes, and attenuated tight junction dysfunction in intestines of cirrhotic rats. LPS decreased TEER in Caco-2 cell monolayer. LPS also decreased claudin-1 and occludin expressions and increased apoptosis in Caco-2 cells. Furthermore, IGF-1 attenuated the effect of LPS on TEER, claudin-1 expression, occludin expression and apoptosis in Caco-2 cells.

Conclusions: Tight junction dysfunction develops during the development of liver cirrhosis, and endotoxemia will develop subsequently. Correspondingly, increased endotoxin in portal system worsens tight junction dysfunction via decreasing intestinal occludin and claudin-1 expressions and increasing enterocytic apoptosis. Endotoxemia and intestinal barrier dysfunction form a vicious circle. External administration of IGF-1 breaks this vicious circle. Improvement of tight junctions might be one possible mechanism of the restoration of intestinal barrier function mediated by IGF-1.

No MeSH data available.


Related in: MedlinePlus